Download Mechanisms underlying skeletal muscle insulin resistance induced

Martins et al. Lipids in Health and Disease 2012, 11:30
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REVIEW
Open Access
Mechanisms underlying skeletal muscle insulin
resistance induced by fatty acids: importance of
the mitochondrial function
Amanda R Martins1, Renato T Nachbar1, Renata Gorjao2, Marco A Vinolo1, William T Festuccia1,
Rafael H Lambertucci2, Maria F Cury-Boaventura2, Leonardo R Silveira1, Rui Curi1 and Sandro M Hirabara1,2*
Abstract
Insulin resistance condition is associated to the development of several syndromes, such as obesity, type 2 diabetes
mellitus and metabolic syndrome. Although the factors linking insulin resistance to these syndromes are not
precisely defined yet, evidence suggests that the elevated plasma free fatty acid (FFA) level plays an important role
in the development of skeletal muscle insulin resistance. Accordantly, in vivo and in vitro exposure of skeletal
muscle and myocytes to physiological concentrations of saturated fatty acids is associated with insulin resistance
condition. Several mechanisms have been postulated to account for fatty acids-induced muscle insulin resistance,
including Randle cycle, oxidative stress, inflammation and mitochondrial dysfunction. Here we reviewed
experimental evidence supporting the involvement of each of these propositions in the development of skeletal
muscle insulin resistance induced by saturated fatty acids and propose an integrative model placing mitochondrial
dysfunction as an important and common factor to the other mechanisms.
Keywords: Skeletal muscle, Insulin resistance, Saturated fatty acids, Mitochondrial dysfunction
Introduction
Insulin resistance is broadly defined as the reduction in
insulin ability to stimulate glucose uptake from body
peripheral tissues. At physiological conditions, insulin
activates glucose uptake by stimulating the canonical
IRS-PI3K-Akt pathway and by phosphorylating and
inactivating Akt substrate 160 (AS160), a protein that,
when activated, prevents glucose transporter (GLUT) 4
translocation to the membrane. Thus, by inhibiting
AS160, insulin promotes the GLUT4 translocation from
inner vesicules, promoting fusion to the plasma membrane and consequently glucose uptake [1].
Although insulin resistance is a key component of several chronic syndromes associated with obesity such as
type 2 diabetes mellitus and metabolic syndrome, the
involved factors and their underlying mechanisms linking excessive adiposity to insulin resistance were not
* Correspondence: [email protected]
1
Department of Physiology and Biophysics, Institute of Biomedical Sciences,
University of São Paulo, Av. Professor Lineu Prestes, 1524, Butantã, São Paulo
05508-000, SP, Brazil
Full list of author information is available at the end of the article
completely elucidated yet [2-5]. Evidence suggests that
fatty acids, whose circulating levels are markedly
increased in obesity and associated-diseases, might play
a role in the development of skeletal muscle insulin
resistance [6,7]. In this sense, prolonged exposure of
skeletal muscle and myocytes to high levels of fatty
acids leads to severe insulin resistance [8,9]. Among the
different types of fatty acids, saturated long-chain fatty
acids such as palmitic and stearic acids were demonstrated to be potent inducers of insulin resistance [5,10].
Several mechanisms have been suggested by us
[2,5,11,12] and others [6,8,13-16] to explain how saturated fatty acids impair insulin actions such as the Randle cycle, accumulation of intracellular lipid derivatives
(diacylglycerol and ceramides), oxidative stress, modulation of gene transcription, inflammation and mitochondrial dysfunction. In the present review, we discuss
evidence supporting the involvement of these mechanisms in the regulation of insulin sensitivity by saturated
fatty acids and propose the mitochondrial dysfunction
found in conditions of elevated fatty acid levels has a
central role in the pathogenesis of insulin resistance.
© 2012 Martins et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
Martins et al. Lipids in Health and Disease 2012, 11:30
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Mechanisms underlying the insulin resistance induced by
saturated fatty acids
Competition between fatty acids and glucose: the randle
cycle
The first mechanistic explanation for the inverse relationship between fatty acids availability and glucose utilization was proposed by Randle et al. [13]. In this
study, it was shown that an elevation in fatty acids supply to diaphragm and isolated heart is associated with
an increase in fatty acid oxidation and an impairment in
glycolytic flux and glucose utilization, such effect being
mediated by alosteric inhibition of glycolytic enzymes.
More specifically, the proposed hypothesis was that
increased fatty acid oxidation raises the production of
acetyl-CoA resulting in inhibition of pyruvate dehydrogenase activity and elevation of citrate levels at the tricarboxylic acid cycle. Citrate together with an increased
ATP/ADP ratio reduce the activity of phosphofructokinase and consequently glucose flux through the glycolytic pathway, resulting in glucose 6-phosphate
accumulation, hexokinase II inhibition, increase in intracellular glucose content and, consequently, reduction in
glucose uptake [17,18].
In accordance with Randle’s hypothesis, elevation in
circulating fatty acids levels by either intralipid/heparin
or lipid infusion in rats, humans and type 2 diabetes
mellitus patients is associated with impairments in glucose uptake, utilization and oxidation in insulin-sensitive
tissues (heart, skeletal muscle and adipose tissue)
[19-21]. Acutely, fatty acids lead to Randle cycle effect,
increasing intracellular content of citrate and glucose-6phosphate and decreasing glycolytic pathway flux [2,11].
It has been also demonstrated that palmitate accutely
increases glucose uptake in L6 myotubes by activating
insulin signaling pathways (Akt and ERK1/2) [22].
However, in contrast to Randle’s hypothesis, in which
intracellular glucose accumulation must precede the
inhibition of glucose uptake, further studies demonstrated that the insulin resistance induced by fatty acids
is primarily associated with impaired glucose uptake
rather than changes in hexose metabolism [8,18]. In studies involving lipid infusion associated with other techniques including glucose and insulin clamp and nuclear
magnetic resonance a rapid reduction in glycolysis (previous to 2 hours) followed by impaired glucose disposal
and glycogen synthesis (between 4-6 hours) was
observed [7,14]. Roden et al. [14] demonstrated that the
reduction in muscle glycogen synthesis is preceded by a
decrease in intramuscular glucose 6-phosphate, suggesting that the increase in plasma fatty acid concentration
initially induces insulin resistance by inhibiting glucose
transport or its phosphorylation. Other studies also
demonstrated that lipid infusion decreases intracellular
glucose and glucose 6-phosphate content, due to
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inhibition of glucose uptake by skeletal muscle [8,23].
These studies demonstrated that Randle cycle does not
completely explain the effects of FFA on glucose metabolism indicating that other mechanisms are also
involved in the FFA-induced insulin resistance.
Inhibition of skeletal muscle insulin signaling
by saturated fatty acids
In addition to its important effects on glucose metabolism directly, saturated fatty acids were demonstrated to
affect insulin intracellular signaling pathways in skeletal
muscle and myocytes [5,14,24,25]. Studies have demonstrated a marked reduction in IRS-1 tyrosine phosphorylation [9], IRS-1 and -2-associated PI3-kinase activity
[9,26], and Akt phosphorylation and activity [26] in skeletal muscle after lipid infusion in euglycemic-hyperinsulinemic clamp. Along with a direct effect of saturated
fatty acids on skeletal muscle insulin signaling, palmitic
acid was shown to decrease insulin receptor expression
and activity [27] and phosphorylation of IRS-1 and -2 at
tyrosine residues [2,28], Akt [5,28-31] and GSK-3, as
reviewed by Schmitz-Peiffer et al. [32] in isolated soleus
muscle, primary culture of rat myocytes, pmi28 myotubes, C2C12 and L6 myocytes. Similarly to skeletal
muscle, palmitic acid inhibits Akt phosphorylation and
activity in rat perfused heart and in HL-1 cells, an
immortalized cardiomyocyte like cell lineage [33].
Several mechanisms have been postulated to account
for the inhibition of insulin signaling by saturated fatty
acids, including the activation of various kinases such as
PKCs, IKK b, JNK, and p38 MAP kinase. These kinases
have been postulated to catalyze the phosphorylation of
serine residues in IRS-1 inhibiting its activity and directing it for degradation by the proteasome [34,35]. Such
effects culminate with a reduction in the phosphorylation of tyrosine residues of IRS-1 by insulin, blocking its
downstream signal transduction [36-38]. Other serine/
threonine kinase activated in high-fat diet-induced or
palmitate-induced insulin resistance is mammalian target of rapamycin (mTOR) [39,40], but the mechanisms
involved are unknown yet.
Lipotoxic intramyocellular lipid accumulation induced by
fatty acids
When the amount of circulating lipids chronically
exceeds white adipose tissue ability for uptake and storage, like obesity, fatty acids accumulate in other tissues
with limited capacity for lipid storage such as liver and
skeletal muscles. Such abnormal ectopic lipid accumulation (lipotoxicity) is strongly associated with insulin
resistance [41,42].
Fatty acids accumulate intracellularly in myocytes
mainly as long-chain fatty acyl-CoA, monoacylglcyerol,
diacylglycerol, phosphatidic acid, triacylglycerol and
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ceramides [32,43-46]. Among these fatty acid derivatives,
high intramyocellular levels of diacylglycerol, triacylglycerol, and ceramides are directly associated with insulin
resistance. Corroborating with this hypothesis, high fat
feeding is associated with an increase in intramyocellular
content of diacylglycerol and triacylglycerol and insulin
resistance, such effects being abolished by inhibition of
muscle lipid accumulation due to genetic deletion of
lipoprotein lipase, fatty acid transporters (CD36 and
FATP1), and diacylglycerol acyl transferase-1 (DGAT-1)
[47-49]. Diacylglycerol accumulation is associated with
the activation of subgroup of novel kinases, members of
the large protein kinase C (PKC) family. Among the
novel kinases, diacylglycerol directly activates PKCθ that
catalyzes the phosphorylation of serine-307 residue at
IRS-1, reducing its tyrosine phosphorylation and activation by insulin.
Consistent with this, Schmitz-Peiffer et al. [50]
reported increased concentration of DAG in rodent’s
muscle and activation of PKCs induced by high-fat diet.
Similarly, infusion of lipid and heparin caused insulin
resistance in muscles that was associated with accumulation of intracellular DAG and specific activation of
PKCθ [8]. Insulin resistance in this model was due to
lipid-induced defects in the insulin signaling pathway
that was caused by a reduction in tyrosine phosphorylation of IRS1, increasing its phosphorylation in serine307 residue [9]. However, there are still no evidence to
explain how the activation of novel PKCs might relate
to serine phosphorylation of IRS1, and which kinases
might have a role in the pathway, as reviewed by Samuel
et al. [51].
In addition to diacylglycerol accumulation, high-fat
diet or palmitate treatment increases production of ceramide and sphingosines in skeletal muscle cells, which is
associated with glucose intolerance and insulin resistance [52,53]. Evidence suggests that ceramide and
phosphatidic acid mediate the deleterious effects of palmitic acid on insulin signaling in cultured myotubes and
insulin mediated Akt and GSK phosphorylation in
C2C12 myotubes [52,54]. Ceramides also affects insulin
signaling by two distinct mechanisms involving the activation of Akt dephosphorylation at threonine 308 and
inhibition of its translocation to the plasma membrane
[55], such effects being dependent on ceramides activation of protein phosphatase 2A (PP2A) and PKCζ,
respectively [56,57]. In addition, glycosylceramide, a glycosyl derivative of ceramides was shown to inhibit insulin receptor activity inducing insulin resistance [56,57].
Recently, it has been demonstrated that increased lysophosphatidylcholine content, a phosphatidic acid, in L6
myotubes treated with palmitate also leads to JNK activation and IRS-1 Ser307 phosphorylation, contributing
to the development of muscle insulin resistance [58].
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Activation of inflammatory signaling pathways by
saturated fatty acids
Saturated fatty acids activate inflammatory signaling
pathways directly through interaction with members of
Toll-like receptor (TLR) family and indirectly through
the secretion of cytokines including TNF-a, IL-1b and
IL-6 [59-61]. TLRs are an evolutionarily ancient pattern-recognition class of receptors that facilitate the
detection of microbes. Saturated fatty acids activate
TLR-4 in skeletal muscle promoting c-Jun NH(2)terminal kinase (JNK) and Ib kinase (IKK) complex
activation, which results in degradation of the inhibitor
of B (IBa) and nuclear factor-B (NFB) activation.
Activation of JNK and IKKb by saturated fatty acids is
associated with a marked inhibition of insulin action
due to the phosphorylation of serine residues on the
insulin IRS-1 and inhibition of its stimulatory phosphorylation of tyrosine residues by the insulin receptor
[62,63]. Corroborating with an important contribution
of TLR-4 to muscle insulin resistance, mice containing
a loss of function by mutation of this receptor are partially protected from fat-induced inflammation and
insulin resistance [64]. In addition, diabetic and obese
mice have increased skeletal muscle IKK and JNK
activities, whose pharmacological and genetic inhibition leads to an improvement in insulin sensitivity and
glucose tolerance [65-67].
Coletta and Mandarino [68] demonstrated that
changes in genes and proteins from inflammatory pathway contribute to the mitochondrial dysfunction
observed in insulin resistant muscle and it can lead to
decreased fat oxidation, ectopic fat accumulation, insulin
signaling abnormalities and finally insulin resistance.
These authors indicate that this mechanism is compatible with and complementary to other hypotheses
regarding the vicious cycle connecting inflammation,
mitochondrial changes, lipid accumulation and insulin
signaling defects. The novel aspect of this mechanism is
that it connects inflammatory processes with changes in
insulin sensitivity by means of altered mechanosignal
transduction due to fibrotic changes.
Fatty acids were also demonstrated to reduce mitochondrial function through induction of pro-inflammatory cytokines. Saturated fatty acids, palmitic and stearic
acids, stimulate the secretion of TNF-a, IL-1b and IL-6
in human leukocytes [60,69]. Wen et al. [61] showed
increased IL-1b production and release by palmitic acid
in macrophages through activation of the NLRP3-ASC
inflammasome. The pro-inflammatory cytokines have
been associated to impaired mitochondrial function,
establishing a link between fatty acids and mitochondrial
dysfunction. Indeed, some studies reported reduced
mitochondrial function in cells exposed to TNF-a, IL1b or IL-6 [70,71].
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Alteration in gene expression by saturated fatty acids
Evidence has been obtained that fatty acids modulate
expression of genes involved in glucose and lipid metabolism. Schmid et al. [72] demonstrated that C57BL/6
mice submitted to high-fat diet present reduced expression of enolase, a glycolytic enzyme, and ATP synthase
in skeletal muscle. In addition, other enzymes of the glycolytic pathway have been shown to be modulated by
fatty acids, such as pyruvate dehydrogenase kinase isozyme 1 (PDK-1), whose expression is increased in pancreatic islets incubated with saturated fatty acids [73],
and lactate dehydrogenase A (LDHA), which was downregulated in white adipose tissue from high-fat-fed animals [74]. Moreover, increased intramyocellular lipid
content has been associated with down-regulation of
PGC-1a and of other genes encoding protein mitochondrial respiratory complexes I, II, III, and IV [75], resulting in impaired mitochondrial biogenesis and function
[76]. Some studies identified transcription factors that
recognize conserved motifs at the promoters of mitochondrial oxidative phosphorylation genes, such as
nuclear respiratory factor (NRF)-1 and GA-binding protein (GABP) (also known as NRF-2) [77]. Studies
showed that the peroxisome proliferator activator receptors (PPARs) control mitochondrial gene subsets, modulating fatty acid oxidation (FAO) and uncoupling
[77,78]. Later, studies showed that PGC-1a is a transcriptional coactivator of NRF-1, GABP, and PPARs,
demonstrating the ability of PGC-1a to integrate physiological signals and to increase mitochondrial biogenesis and oxidative function [79,80]. Thus, a reduction of
PGC-1a content in conditions of high fatty acid levels
might be associated with impairment of mitochondrial
function [5,76]. In addition, insulin-resistant subjects
have reduced expression of mitochondrial genes, such as
cytochrome c oxidase and complexes I and III subunits
of the electron transport chain [81]. Activities of carnitine palmitoyltransferase-1 (CPT-1) and other key mitochondrial enzymes, such as citrate synthase and bhydroxyacyl-CoA dehydrogenase, have also been found
decreased in skeletal muscle from obese and type 2 diabetic individuals [26,82,83]. These changes in gene
expression and enzyme activities induced by fatty acids
contribute to the reduced mitochondrial oxidative capacity consequently leading to mitochondrial dysfunction.
Increase in reactive oxygen species by
saturated fatty acids
Type 2 diabetes mellitus, obesity and the metabolic syndrome are strongly correlated with increased skeletal
muscle content of reactive oxygen species (ROS)
[84-86]. All conditions cited above contribute to an oxidative environment, modulating insulin sensitivity either
by increasing insulin signaling or impairing glucose
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tolerance. The mechanisms by which this occurs are
often multifactorial and complex, involving several cell
signaling pathways [87].
Production of ROS can occur in response to diverse
stimuli including: (1) intracellular factors, such as nutrient metabolism, endoplasmic reticulum stress, and
detoxification of various xenobiotics; (2) extracellular
factors like signaling through plasma membrane receptors, such as hormones and growth factors and by proinflammatory cytokines; and (3) physical-environmental
factors (e.g. ultraviolet irradiation) [88-91]. When moderately produced, ROS are involved in important physiological processes that lead to desired cellular responses.
However, high ROS production is negatively associated
with different biological signaling pathways [87]. ROS
can react with multiple cellular components, such as
proteins, lipids and nucleic acids, generating reversible
or irreversible oxidative modifications. Pathophysiological processes mediated by ROS are more likely to induce
irreversible modifications in cellular components, a reasonable definition of the term oxidative stress [88].
Control of vascular tone, cell adhesion, immune
responses, and growth factors and hormone action are
examples of ROS participation in normal physiology
[92,93]. Conversely, a negative role of ROS has been
implicated in ageing-related diseases, malignant transformation, atherosclerosis, neurodegenerative diseases, obesity, and diabetes [88,94,95]. Insulin signaling can be
also impaired by oxidative stress, but the mechanisms
involved are not fully understood. Studies have been
demonstrated that ROS lead to impaired insulin
response by inducing IRS serine/threonine phosphorylation, decreasing GLUT4 gene transcription, and decreasing mitochondrial activity [37,96].
Chronic elevation in plasma lipids levels and excessive
intramyocellular fatty acid disposal are characterized by
increased ROS and reactive nitrogen species (RNS) production [15,97,98]. Diet-induced obese mice have an
increased expression of inducible nitric oxide synthase
(iNOS) and RNS generation in skeletal muscle such
effects being associated with impaired insulin sensitivity
[15,99], since mice with iNOS disruption in muscle are
protected from insulin resistance induced by obesity
[100,101]. Diabetic patients present elevated ROS production in endothelial cells through NADPH oxidase
activation, a mechanism mediated by PKC [102].
NADPH-oxidase complex is also found in skeletal muscles, raising the possibility that a similar mechanism
occurs under elevated FA availability. Our group
recently demonstrated that palmitate induces superoxide
production in cultured skeletal muscle cells via NADPH
oxidase activation, at least in part [98]. Some evidence
also links xanthine oxidase (XO) as a source of
increased ROS generation in diabetes and obesity. XO
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protein and activity is found increased in muscle arterioles and livers from animal models of type 1 diabetes
and diet-induced obesity [88,103,104].
Animals treated either with high-fat diet or oxidant
drugs such as buthionine sulfoximine (BSO), an inhibitor of gluthatione synthase, have increased skeletal muscle ROS production, oxidative stress and are insulinresistant [105,106]. On the other hand, animals food
restricted or treated with antioxidant drugs such as Nacetyl-cysteine (NAC), lipoic acid, vitamin E, and taurine, have reduced oxidative stress and improved insulin
sensitivity [106-108]. In addition, mice overexpressing
SOD2 have decreased ROS levels, improved hepatic
insulin sensitivity, normalization of blood glucose and
insulin levels, and reduced activation of cellular stress
signalling pathways [109]. These data suggest that mitochondrial ROS is important for the development of
insulin resistance.
The involvement of oxidative stress in insulin resistance was also observed in studies performed in myocytes. In L6 muscle cells, H 2 O 2 reduced insulinstimulated glucose uptake and glutathione content,
effects that were prevented by preincubation with the
antioxidant lipoic acid [110]. Rat soleus muscle exposed
to nitric oxide (NO) donors have decreased insulin-stimulated glucose uptake and glycogen synthesis, effects
that were associated with reduced insulin-stimulated
phosphorylation of IR, IRS-1, and Akt [15].
Since mitochondria is the main site of ROS production in skeletal muscle, mitochondrion DNA, protein
and lipids components are exposed to high levels of
these metabolites suffering structural modification and
damage which at long term can result in impaired function of this organelle [111,112].
Mitochondrial dysfunction or reduced mitochondrial
biogenesis and density can lead to a decrease in mitochondrial fatty acids oxidation, which results in
increased levels of fatty acil-CoA and DAG that can
activate stress-related Ser/Thr kinase activity and inhibit
glucose transport, as reviewed by Lowell and Shulman
[113].
In the case of stress-activated kinases, oxidative stress
also contributes to impair insulin signaling by increased
uncoupling protein-2 (UCP-2) activity. When these proteins are activated, it results in a heat generation that
does not contribute to ATP production [114,115]. UCP2 negatively regulates glucose-stimulated insulin secretion by reducing the ATP production, which is key to
provide energy for almost all cellular processes [113]. In
addition, UCP-2-/- mice demonstrate enhanced insulin
secretory capacity after a high-fat diet due to improved
b-cell functions in a type 2 diabetes animal model [116].
Mitochondrial uncoupling is a powerful tool to control ROS formation and consequently to preserve
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mitochondrial function. It can be hypothesized that
fatty-acid induced uncoupling decrease mitochondrial
ROS production and thus it can prevent mitochondrial
lipotoxicity. In fact, UCP-3 is upregulated using high-fat
diets [117,118], fasting [119], etomoxir treatment (which
inhibits the mitochondrial fatty acid oxidation) [120,121]
and lipid infusion [122], all conditions being associated
with excessive lipid accumulation in skeletal muscle. On
the other hand, when fat oxidative capacity is improved,
like with endurance training [123,124], weight loss
[125], or lowering circulatory fatty acids [126,127] there
is a decrease in UCP-3. Interestingly, UCPs are activated
by fatty acids and/or its peroxidation products, reducing
mitochondrial ROS production [128,129]. So, it can be
suggested that UCP-3 is involved in the protection
against mitochondrial lipotoxicity by decreasing ROS
production when activated by FA, as reviewed by
Schrauwen et al. [130].
In summary, oxidative stress seems to play an important role in mitochondrial dysfunction, which can
further exacerbate stress signals and reduce ATP production. The pathways leading to insulin resistance may
be synergistic and mitochondrial dysfunction can create
a feedback loop, adding to the overall oxidative stress
environment [87].
Impairment of skeletal muscle mitochondrial function
by saturated fatty acids
Several studies have shown that mitochondrial content,
mitochondrial function, and oxidative capacity are
decreased in insulin-resistant obese and type 2 diabetic
individuals [131,132] suggesting that mitochondrial dysfunction might play an important role in the pathophysiology of insulin resistance. Corroborating with this
hypothesis, impaired mitochondrial function and
reduced fatty acid oxidative capacity were found in isolated primary myocytes, isolated rectus abdominal muscle strips and muscle homogenates from insulinresistant obese and type 2 diabetic patients [26,83,133].
Moreover, mitochondrial density is reduced in insulinresistant skeletal muscle from children, offspring of people with type 2 diabetes, suggesting that impaired mitochondrial oxidative capacity can be an inherited defect
and an early marker for the development of insulin
resistance [96]. Some studies have also reported alterations (mutations, polymorphisms, and epigenetics) in
the mitochondrial DNA in conditions of insulin resistance, such as obesity, type 2 diabetes, and metabolic
syndrome [134-137].
Evidence points for an important role of fatty acids in
the genesis of the mitochondrial dysfunction associated
with obesity and type 2 diabetes mellitus. In this sense,
lipid infusion or administration of high-fat diet to health
human and rodents were associated with impaired
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mitochondrial function characterized by a reduction in
ATP synthesis, oxygen consumption and oxidative phosphorylation [16,75,138,139]. These findings were corroborated by in vitro studies in which treatment of
cultured skeletal muscle cells with palmitic acid
increased ROS production, impaired fatty acid oxidation
and decreased PGC-1 expression [103,104,140,141]. Studies from our group demonstrated that saturated fatty
acids directly induces mitochondrial dysfunction in
C2C12 skeletal muscle cells, as evidenced by reduced
ATP synthesis and mitochondrial polarization [5].
Mitochondrial dysfunction plays a central role in the fatty
acid-induced insulin resistance
As discussed above, several mechanisms have been proposed to explain the insulin resistance induced by saturated fatty acids. All these mechanisms operate in
coordinated, integrated manner linking fatty acids availability to skeletal muscle insulin resistance. To account
for this multifactorial characteristic of saturated fatty
acid actions, we propose herein an integrative model
centered on mitochondrial dysfunction as an important
factor in the genesis of insulin resistance induced by
fatty acids (Figure 1).
In physiological conditions, fatty acids are normally
and rapidly oxidized with low ROS production, little
intracellular lipid accumulation and preservation of
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insulin sensitivity (Figure 1A). In pathological conditions, chronic elevation in circulating fatty acid levels
reduces the expression of genes involved in mitochondrial biogenesis oxidative capacity and increase production of ROS, impairing mitochondrial biogenesis and
function (Figure 1B). As a consequence, oxidative capacity is impaired and mitochondrial mass is reduced,
increasing still further ROS production, leading to accumulation of fatty acid-derived metabolites such as diacylglycerol and ceramides.
ROS and lipid metabolites have been positively associated with insulin resistance and activation of several
kinases, such as NFB, p38 MAP kinase, JNK, and some
novel and atypical PKC isoforms, as PKC-ζ and -ε, in
skeletal muscle [27,36,50,141-144]. These kinases impair
the insulin signaling pathway by inducing serine/threonine phosphorylation in IRS-1. Under this condition,
insulin-stimulated tyrosine phosphorylation of IRS-1 is
inhibited, impairing activation of downstream signaling
pathways and decreasing glucose uptake and metabolism
in response to the hormone [5,6,145,146] (Figure 2).
Concluding remarks
We discussed herein the mechanisms involved in insulin
resistance in skeletal muscle cells induced by high availability of FFA. Several mechanisms have been proposed,
such as Randle cycle, inhibition of insulin signaling
Figure 1 Role of mitochondria in the insulin resistance induced by free fatty acids (FFA). In the normal condition (A), mitochondrial
function is normal and FFA are rapidly metabolized with low reactive oxygen species (ROS) production and without accumulation of lipid
metabolites; normal insulin response is preserved in this condition. In pathological condition (B), the excess of plasma FFA levels induces high
FFA uptake into the cell, modulating negatively the expression of genes related to mitochondrial biogenesis and oxidative capacity, and into the
mitochondrion, increasing the electron flux through to electron transport chain and, consequently, ROS and RNS production. As a result,
mitochondrial biogenesis and function are impaired, decreasing mitochondrial mass and oxidative capacity, leading to abnormal intracellular
accumulation of lipid metabolites and ROS and RNS, which activate some protein kinases involved in the phosphorylation of IRS-1 on threonine
and serine residues. When phosphorylated in threonine and serine residues, IRS-1 is not phosphorylated on tyrosine residues, preventing
activation of downstream signalling pathways by insulin. In addition, RNS increases IRS-1 nitrosilation, resulting in high degradation of these
protein, which can contribute to impaired insulin response
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Received: 4 January 2012 Accepted: 23 February 2012
Published: 23 February 2012
Figure 2 Mechanisms underlying insulin resistance by impaired
mitochondrial function.
pathway, regulation of gene expression and enzymatic
activities, increase in ROS and RNS production, and
impairment in mitochondrial function. Although numerous studies have been performed in order to investigate
each one of these mechanisms, the conclusive proposition has not been defined yet. Evidence suggests that
these mechanisms are not exclusive and there are several data in the literature pointing out that more than
one mechanism is involved in the insulin resistance
induced by FFA. We proposed herein a unifying hypothesis that places the importance of mitochondria in the
establishment of FFA-induced insulin resistance.
Acknowledgements
This study is supported by grants from FAPESP, CAPES, CNPq/National
Institute of Sciences and Technology in Obesity and Diabetes, and Center of
Lipid Research And Education (CLEAR).
Author details
1
Department of Physiology and Biophysics, Institute of Biomedical Sciences,
University of São Paulo, Av. Professor Lineu Prestes, 1524, Butantã, São Paulo
05508-000, SP, Brazil. 2Post-Graduate Program in Human Movement Sciences,
Institute of Physical Activity Sciences and Sports, Cruzeiro do Sul University,
São Paulo, SP, Brazil.
Authors’ contributions
ARM, RTN, and RHL participated of the acquisition, analysis, and
interpretation of the data from literature. RG, MAV, and WTF organized the
structure of the manuscript and had substantial contribution to the
conception and design. MFCB and LRS were involved in the drafting of the
manuscript and figures. SMH and RC critically revised the text and figures for
the final version of the manuscript. All authors read and approved the final
manuscript.
Competing interests
The authors declare that they have no competing interests.
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doi:10.1186/1476-511X-11-30
Cite this article as: Martins et al.: Mechanisms underlying skeletal
muscle insulin resistance induced by fatty acids: importance of the
mitochondrial function. Lipids in Health and Disease 2012 11:30.
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